HIV-1 and HIV-2 are transmitted predominantly by sexual contact which involves exposure to mucosal surfaces. Previous HIV vaccine studies have focused on immunization and challenge by parenteral (IV or IM) routes using cell-free virus. This proposal will develop vaginal immunization and challenge with cell-associated virus using the SIV - rhesus macaque model of HIV infection. This model is most appropriate because the genital challenge technique is well defined, research animals are readily available and the studies can be performed economically. In this proposal we aim: 1) to identify the initial target cells in the vaginal mucosa after exposure to cell-associated virus and to determine the mechanism of virus spread to regional and systemic lymphoid tissue, and 2) to determine whether perivaginal immunization with replicating or nonreplicating SIV can generate immune responses which will protect against infection or will alter the dissemination of cell-associated SIV administered vaginally. In addition, we will determine if the immune responses which protect against vaginal challenge will also protect against SIV-infected cells inoculated intravenously. The early events of SIV infection in the genital tract leading to systemic infection will be studied, including the induction of humoral and cellular immune responses. Perivaginal immunization of female rhesus macaques with SIV immunogens will aim to stimulate local immune responses that stop the infectious process in its early stages and prevent persistent infection. Then the efficacy of vaginal immunization against IV challenge will be determined. The results of these experiments will define parameters of host immunity that are necessary for preventing the sexual transmission of HIV.